TY - JOUR
T1 - BLIMP1 transcriptionally induced by EGFR activation and post-translationally regulated by proteasome and lysosome is involved in keratinocyte differentiation, migration and inflammation
AU - Chang, Hua Ching
AU - Huang, Duen Yi
AU - Wu, Nan Lin
AU - Kannagi, Reiji
AU - Wang, Li Fang
AU - Lin, Wan Wan
N1 - Funding Information:
This work was supported by research grants from Academia Sinica, Taiwan (IBMS-CRC103-P01) and Ministry of Science and Technology, Taiwan (MOST 107-2320-B-002-036-MY3).
Publisher Copyright:
© 2018 Japanese Society for Investigative Dermatology
PY - 2018/11
Y1 - 2018/11
N2 - Background: B lymphocyte-induced maturation protein-1 (BLIMP1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of BLIMP1 expression in keratinocytes and crosstalk between EGFR and BLIMP1 in skin homeostasis. Objective: The aim of the study was to investigate the regulation and functional link between EGFR and BLIMP1 in human epidermal keratinocytes. Methods: Immunoblotting and Q-PCR were used to determine the molecular mechanism of BLIMP1 expression induced by EGFR in primary human epidermal keratinocytes (NHEK) and HaCaT cells. In functional assay, effects of BLIMP1 knockdown on EGFR-mediated cytokine production, differentiation, and migration in NHEK were evaluated by Q-PCR, ELISA, immunoblotting, and/or wound-healing assay. Results: EGFR activation by EGFR ligands could upregulate the protein and mRNA levels of BLIMP1 in NHEK and HaCaT cells. This effect was dependent on PKC, p38, and ERK activation. Additionally, the stability of BLIMP1 protein was under the control of the proteasome and lysosome degradation systems. EGF could also upregulate BLIMP1 expression in skin squamous cell carcinomas. In addition, BLIMP1 knockdown enhanced the EGFR-mediated IL8, CXCL5 and IL6 gene expression and keratinocyte migration, but reduced the EGFR-mediated suppression of differentiation marker K10. Conclusions: Our findings shed new insights into the regulation of BLIMP1 expression by EGFR-mediated gene transcription and proteasome/lysosome-mediated degradation in keratinocytes. Functionally, BLIMP1 is a negative regulator of EGF-induced inflammation and migration in keratinocytes, and exerts a gene-specific regulation on keratinocyte differentiation.
AB - Background: B lymphocyte-induced maturation protein-1 (BLIMP1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of BLIMP1 expression in keratinocytes and crosstalk between EGFR and BLIMP1 in skin homeostasis. Objective: The aim of the study was to investigate the regulation and functional link between EGFR and BLIMP1 in human epidermal keratinocytes. Methods: Immunoblotting and Q-PCR were used to determine the molecular mechanism of BLIMP1 expression induced by EGFR in primary human epidermal keratinocytes (NHEK) and HaCaT cells. In functional assay, effects of BLIMP1 knockdown on EGFR-mediated cytokine production, differentiation, and migration in NHEK were evaluated by Q-PCR, ELISA, immunoblotting, and/or wound-healing assay. Results: EGFR activation by EGFR ligands could upregulate the protein and mRNA levels of BLIMP1 in NHEK and HaCaT cells. This effect was dependent on PKC, p38, and ERK activation. Additionally, the stability of BLIMP1 protein was under the control of the proteasome and lysosome degradation systems. EGF could also upregulate BLIMP1 expression in skin squamous cell carcinomas. In addition, BLIMP1 knockdown enhanced the EGFR-mediated IL8, CXCL5 and IL6 gene expression and keratinocyte migration, but reduced the EGFR-mediated suppression of differentiation marker K10. Conclusions: Our findings shed new insights into the regulation of BLIMP1 expression by EGFR-mediated gene transcription and proteasome/lysosome-mediated degradation in keratinocytes. Functionally, BLIMP1 is a negative regulator of EGF-induced inflammation and migration in keratinocytes, and exerts a gene-specific regulation on keratinocyte differentiation.
KW - BLIMP1
KW - Differentiation
KW - EGFR
KW - Inflammation
KW - Keratinocyte
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U2 - 10.1016/j.jdermsci.2018.08.011
DO - 10.1016/j.jdermsci.2018.08.011
M3 - Article
C2 - 30197274
AN - SCOPUS:85054493246
SN - 0923-1811
VL - 92
SP - 151
EP - 161
JO - Journal of Dermatological Science
JF - Journal of Dermatological Science
IS - 2
ER -